Sin3A is a general transcription co-regulatory factor and commonly acts as a scaffold protein assembling the DNA-binding TFs, HDACs and other chromatin-modifying enzymes into a large complex, which facilitates transcription repression through changing the chromatin compaction. Moreover, some functions of TGIF1 independent of DNA binding were also evidenced in TGFβ, nuclear receptor and Wnt signaling pathways. Following DNA binding via the HD, TGIF1 recruits corepressor CtBP1/2 through RD1 containing a conserved “PLDLS” motif and/or Sin3A and HDACs through RD2, leading to the change of chromatin state and thereby transcription repression. TGIF1 HD binds to gene promoters containing a consensus sequence of 5’-TGTCA-3′, and thousands of genes have been identified to be directly regulated by TGIF1. Three major functional domains including HD and repressive domains 1 and 2 (RD1/2) have been demonstrated in TGIF1 ( Figure 1A).

TGIF1 was initially identified to contain 272 amino acid residues (isoform a, high-abundant form), while the following study further identified a variety of TGIF1 isoforms resulting from mRNA alternative splicing, with the longest one containing 401 residues (isoform c). TGIF1 functions mainly as a DNA-binding transcription repressor that interacts with general corepressors, including CtBP1/2, Sin3A and histone deacetylases (HDACs). This study provides a structural insight into the binding of TGIF1 with SIN3A, improves the knowledge of the structure–function relationship of TGIF1 and its homologs and will help in recognizing an undiscovered SIN3A-PAH2 binder and developing a peptide inhibitor for cancer treatment. Moreover, homodimerization of TGIF1 through the SID and key residues of F379, 元82 and V383 was evidenced, which suggests a dual role of TGIF1 SID and a correlation between dimerization and SIN3A-PAH2 binding. Residues F379, 元82 and V383 of TGIF1 buried in the hydrophobic core of the complex are critical for the binding. The TGIF1 SID adopts a disordered structure at the apo state but forms an amphipathic helix binding into the hydrophobic cleft of SIN3A PAH2 through the nonpolar side at the holo state. Here, we demonstrate that TGIF1 utilizes a C-terminal domain (termed as SIN3A-interacting domain, SID) to bind with SIN3A PAH2.

However, to date, the exact region of TGIF1 binding to SIN3A was not clear, and the structural basis for the binding was unknown. TGIF1-directed transcriptional repression of specific genes depends on the recruitment of corepressor SIN3A. TGIF1 is a transcriptional repressor playing crucial roles in human development and function and is associated with holoprosencephaly and various cancers.

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